TuberculosisNCT02380508
Heterologous Effects of BCG in Healthy UK Adults
A study testing BCG SSI, No vaccination and BCG Sii in people with Tuberculosis, run by University of Oxford at 3 sites in United Kingdom.
Trial summary
TB038 is a clinical study to assess the non-specific effects of BCG vaccination and gain a better understanding of how the body's immune system reacts to BCG and in turn potentially prevents infection from other bacteria. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Tuberculosis
- What is being tested?
- BCG SSI, No vaccination and BCG Sii
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 3 sitesUnited Kingdom
- Study dates
- Feb 2015to Nov 2016
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Volunteers must meet all of the following criteria to enter the study:
- Healthy adult aged 18-45 years
- BCG naïve
- Resident in or near Oxford (for CCTVM and John Warin Ward) or Birmingham (for NIHR WTCRF) for the duration of the study period
- No relevant findings in medical history or on physical examination
- Allow the Investigators to discuss the volunteer's medical history with their GP
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- Use effective contraception for the duration of the study period (females only)
- Agreement to refrain from blood donation during the duration of the study and for a period of 3 months after their last visit
- Give written informed consent
- Allow the Investigator to register volunteer details with a confidential database to prevent concurrent entry into clinical trials or studies
- Able and willing (in the Investigator's opinion) to comply with all the study requirements
Who cannot join
- Volunteers must meet none of the following criteria to enter the study:
- Laboratory evidence at screening of latent M. tb infection as indicated by a positive IGRA response
- Clinical, radiological, or laboratory evidence of current active TB disease
- Previous vaccination with BCG, or any candidate TB vaccine
- Within the last year had close household contact with an individual with smear positive pulmonary tuberculosis
- Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse
Show all 17Show fewer
- History of serious psychiatric condition
- Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents
- Concurrent use of long term antibiotic therapy
- History of anaphylaxis to vaccination or any allergy likely to be exacerbated by any component of the BCG vaccine
- Any abnormality of screening blood or urine tests that is deemed to be clinically significant or that may compromise the safety of the volunteer in the study
- Positive HBsAg, HCV or HIV antibodies
- Female confirmed pregnant or intention to become pregnant during study period, or currently lactating
- Current involvement in another study or trial that involves regular blood tests or an investigational medicinal product
- Use of an investigational medicinal product or non-registered drug, live vaccine, or investigational medical device for four weeks prior to dosing with the study vaccine
- Administration of immunoglobulins and/or any blood products within the three months preceding the planned challenge date
- Any other significant disease, disorder, or finding, which, in the opinion of the Investigator, may either put the volunteer at risk, or may influence the result of the study, or may affect the volunteer's ability to participate in the study
Trial locations and contacts
3 sites in 1 country.
United Kingdom3 sites
NIHR Wellcome Trust Clinical Research Facility, University of Birmingham
Birmingham, West Midlands, B15 2TH
Centre for Clinical Vaccinology and Tropical Medicine , University of Oxford
Oxford, Oxfordshire, OX3 7LE
Oxford University Hospitals- John Warin Ward, University of Oxford
Oxford, Oxfordshire, OX3 7LE
About this study
Official title: Evaluation of the Heterologous Effects of Bacille Calmette-Guérin (BCG) Vaccination in Healthy UK Adults
TB038 is a clinical study to assess the non-specific effects of BCG vaccination and gain a better understanding of how the body's immune system reacts to BCG and in turn potentially prevents infection from other bacteria.
Read the detailed description
Since 1927, it has been observed that BCG-vaccinated neonates have lower all-cause mortality rates. This heterologous or non-specific effect within the first 6-12 months of life has been demonstrated in randomised and observational studies in low income countries with high childhood mortality rates. The most consistent effect is reduced neonatal mortality due to fewer cases of neonatal sepsis, respiratory infection and fever. The main limitation of these studies is the risk of confounding inherent in their cross sectional and observational designs. It is essential that we determine the cogency of this effect, as potential BCG replacement vaccines must be non-inferior to BCG in this regard.
There is a plausible rationale that BCG, a replicating mycobacterium, is capable of inducing non-specific innate immunity, which could induce protection against disease and death from non-mycobacterial infections early in life. For example, intravesical BCG is an effective treatment for bladder cancer, an effect presumed to be non-specific and innate. However, our understanding of the immunological mechanisms involved is incomplete. Data is needed from robust experiments to quantify any causal relationship between infant survival and BCG vaccination. Demonstrating an effect of recent BCG vaccination on the growth of common bacterial pathogens involved in neonatal sepsis, using whole blood in an in-vitro human model, would provide evidence to support a randomised controlled trial in infants in TB high burden countries and would impact on public health vaccination scheduling. In addition it would provide us with an in-vitro model by which to assess future BCG replacement vaccines.
Healthy BCG naïve adults in the UK have been selected for this study because of their low baseline level of anti-mycobacterial immunity and therefore reduced ability to suppress BCG growth. Whilst the target population for the heterologous effects of BCG vaccination is infants, the blood volume required in order to optimise the GIA would not be possible to collect from infants. Therefore by undertaking this work in healthy BCG naïve UK adults we can obtain the blood volumes required for this exploratory work in a population of individuals with a similar background mycobacterial exposure to infants in TB high burden, low income countries.
Volunteers in this study will receive BCG vaccination at the standard dose of 2-8x10^5 cfu. BCG SSI containing Mycobacterium bovis strain Danish 1331 is preferred as it is licensed in the UK for vaccination. However BCG SSI can frequently go into short supply globally with impact on UK supply. In the event of this occurring, BCG vaccine supplied by the Sii (Serum institute of India) will be used instead which contains Mycobacterium bovis BCG strain Moscow 361 I and is on the WHO list of prequalified vaccines. The same strain will be used for all volunteers.
- Conditions
- Tuberculosis
- Being tested
- BCG SSI, No vaccination, BCG Sii
- Keywords
- BCG study
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BCG SSIDrug
Also called Bacille Calmette-Guérin Statens Serum Institute (BCG SSI)
Intradermal injection
No vaccinationOther
BCG SiiDrug
Also called Bacille Calmette-Guérin Serum Institute of India
intradermal injection
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | 32 BCG-naïve subjects receiving BCG SSI or BCG Sii at standard dose (2-8x10^5 cfu) via Intradermal route. Receives: Drug: BCG SSI; Drug: BCG Sii |
| Group 2 | Experimental | 8-16 control volunteers receiving no vaccination. Receives: Other: No vaccination |
What is being measured
The primary outcome is the main question the study is designed to answer.
Growth inhibition assays
Determine the heterologous effects of BCG vaccination in healthy UK adults using in-vitro Growth Inhibition Assays as a surrogate marker to assess the individuals' capacity to control growth of S. aureus, K. pneumonia, Group B streptococci and E.coli.
Measured: Up to Day 84
Secondary outcomes (1)
Immune response markers
Evaluation of laboratory markers of the immune response that correlate with levels of bacterial growth inhibition identified using the in-vitro GIAs.
Measured: Up to Day 84
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2015 (estimated)
- Study startFeb 2015
- Primary completionNov 2016
- Study completionNov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Helen McShane, Study director, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02380508
- Sponsor's protocol ID
- TB038
- Status last verified
- Oct 2016
- First submitted
- 3 Feb 2015
- Last updated
- 30 Nov 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
Wilkie M, Tanner R, Wright D, Lopez Ramon R, Beglov J, Riste M, Marshall JL, Harris SA, Bettencourt PJG, Hamidi A, van Diemen PM, Moss P, Satti I, Wyllie D, McShane H. Functional in-vitro evaluation of the non-specific effects of BCG vaccination in a randomised controlled clinical study. Sci Rep. 2022 May 12;12(1):7808. doi: 10.1038/s41598-022-11748-x.
PubMed 35552463
Study at a glance
From the registry record, last updated by the sponsor on 30 Nov 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Heterologous Effects of Bacille Calmette-Guérin (BCG) Vaccination in Healthy UK Adults
- ClinicalTrials.gov ID
- NCT02380508
- Acronym / sponsor ID
- TB038
- Conditions
- Tuberculosis
- Keywords
- BCG study
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- Feb 2015
- Primary completion
- Nov 2016 (actual)
- Study completion
- Nov 2016 (actual)
- First posted
- 5 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
TB038 is a clinical study to assess the non-specific effects of BCG vaccination and gain a better understanding of how the body's immune system reacts to BCG and in turn potentially prevents infection from other bacteria.
Detailed description
Since 1927, it has been observed that BCG-vaccinated neonates have lower all-cause mortality rates. This heterologous or non-specific effect within the first 6-12 months of life has been demonstrated in randomised and observational studies in low income countries with high childhood mortality rates. The most consistent effect is reduced neonatal mortality due to fewer cases of neonatal sepsis, respiratory infection and fever. The main limitation of these studies is the risk of confounding inherent in their cross sectional and observational designs. It is essential that we determine the cogency of this effect, as potential BCG replacement vaccines must be non-inferior to BCG in this regard.
There is a plausible rationale that BCG, a replicating mycobacterium, is capable of inducing non-specific innate immunity, which could induce protection against disease and death from non-mycobacterial infections early in life. For example, intravesical BCG is an effective treatment for bladder cancer, an effect presumed to be non-specific and innate. However, our understanding of the immunological mechanisms involved is incomplete. Data is needed from robust experiments to quantify any causal relationship between infant survival and BCG vaccination. Demonstrating an effect of recent BCG vaccination on the growth of common bacterial pathogens involved in neonatal sepsis, using whole blood in an in-vitro human model, would provide evidence to support a randomised controlled trial in infants in TB high burden countries and would impact on public health vaccination scheduling. In addition it would provide us with an in-vitro model by which to assess future BCG replacement vaccines.
Healthy BCG naïve adults in the UK have been selected for this study because of their low baseline level of anti-mycobacterial immunity and therefore reduced ability to suppress BCG growth. Whilst the target population for the heterologous effects of BCG vaccination is infants, the blood volume required in order to optimise the GIA would not be possible to collect from infants. Therefore by undertaking this work in healthy BCG naïve UK adults we can obtain the blood volumes required for this exploratory work in a population of individuals with a similar background mycobacterial exposure to infants in TB high burden, low income countries.
Volunteers in this study will receive BCG vaccination at the standard dose of 2-8x10^5 cfu. BCG SSI containing Mycobacterium bovis strain Danish 1331 is preferred as it is licensed in the UK for vaccination. However BCG SSI can frequently go into short supply globally with impact on UK supply. In the event of this occurring, BCG vaccine supplied by the Sii (Serum institute of India) will be used instead which contains Mycobacterium bovis BCG strain Moscow 361 I and is on the WHO list of prequalified vaccines. The same strain will be used for all volunteers.
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Drug: BCG SSI, Drug: BCG Sii32 BCG-naïve subjects receiving BCG SSI or BCG Sii at standard dose (2-8x10^5 cfu) via Intradermal route. |
| Group 2 | Experimental | Other: No vaccination8-16 control volunteers receiving no vaccination. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- Healthy adult aged 18-45 years
- BCG naïve
- Resident in or near Oxford (for CCTVM and John Warin Ward) or Birmingham (for NIHR WTCRF) for the duration of the study period
- No relevant findings in medical history or on physical examination
- Allow the Investigators to discuss the volunteer's medical history with their GP
Key exclusion criteria (17 listed)
- Laboratory evidence at screening of latent M. tb infection as indicated by a positive IGRA response
- Clinical, radiological, or laboratory evidence of current active TB disease
- Previous vaccination with BCG, or any candidate TB vaccine
- Within the last year had close household contact with an individual with smear positive pulmonary tuberculosis
- Clinically significant history of skin disorder, allergy, immunodeficiency (including HIV), cancer (except BCC or CIS), cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, neurological illness, psychiatric disorder, drug or alcohol abuse
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BCG SSIAlso: Bacille Calmette-Guérin Statens Serum Institute (BCG SSI)Intradermal injection | Drug | Group 1 |
| No vaccination | Other | Group 2 |
| BCG SiiAlso: Bacille Calmette-Guérin Serum Institute of Indiaintradermal injection | Drug | Group 1 |
Primary outcome
Growth inhibition assays
Time frame: Up to Day 84
Determine the heterologous effects of BCG vaccination in healthy UK adults using in-vitro Growth Inhibition Assays as a surrogate marker to assess the individuals' capacity to control growth of S. aureus, K. pneumonia, Group B streptococci and E.coli.
1 secondary outcome
Immune response markers
Time frame: Up to Day 84
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Nov 2016.
- Derived from this study: PubMed 35552463Wilkie M, Tanner R, Wright D, Lopez Ramon R, Beglov J, Riste M, Marshall JL, Harris SA, Bettencourt PJG, Hamidi A, van Diemen PM, Moss P, Satti I, Wyllie D, McShane H. Functional in-vitro evaluation of the non-specific effects of BCG vaccination in a randomised controlled clinical study. Sci Rep. 2022 May 12;12(1):7808. doi: 10.1038/s41598-022-11748-x.
- Jenner Institute Clinical TrialsLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Helen McShane study director
University of Oxford
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing BCG SSI, No vaccination and BCG Sii in people with Tuberculosis, run by University of Oxford at 3 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Nov 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Growth inhibition assays (time frame: Up to Day 84). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02380508, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2016.